This multidisciplinary effort of experts in biomarker research proposes to renew their commitment to the EDRN and to lead our Clinical Validation Center ever closer to impacting patient care. Therefore we propose to test best candidate biomarkers of lung cancer developed at our and other institutions for added value in the assessment of the risk for, and diagnosis of, lung cancer compared to the standard of care. The hypothesis is that addition of imaging and molecular biomarkers measured by chest computed tomography and in the sputum, the bronchial epithelium and blood, likely in a multivariable manner, could improve the identification of high risk individuals for lung cancer and improve CT screening overall results by reducing false-positive tests. We propose a three way approach. First we will test candidate biomarkers for lung cancer development in an observational study of selected very high risk individuals from the Nashville community performing repeated measurements of clinical, imaging (low-dose chest CT) variables, as well as molecular biomarker signatures, some of which will be obtained from bronchoscopy. Second, we propose to validate the most promising diagnostic candidate signatures to each test in carefully designed prospective study of individuals presenting with indeterminate pulmonary nodules. Third, we will test a novel molecular imaging tracer in a population of intermediate and high risk lung nodules. This tracer will be compared to standard of care FDG PET, and if significantly better, should have huge impact on the management of lung nodules. Our CVC will also centralize an effort to collect and store pertinent clinical data and tissues (blood, urine, and the airways specimens) and make these resources available to the community and to collaborators within and outside of the EDRN program, including the industry partners.